The 4-bromo-2-oxyimino butyric acid and its derivatives of formula (I), wherein R is hydrogen or a protective group are generally prepared by two methods, both starting from diketene of formula (IV)
Method 1: By step-wise bromination of the 2-oxyimino-3-oxo butyric acid derivatives of formula (II), wherein R is as defined above and R1 together with the carboxylic acid group (—COO) to which it is attached forms a carboxylic acid ester group and hydrolysis of the ester group R1 or simultaneous bromination and hydrolysis in one step.
The compounds of formula (II) in turn are obtained by oxyimination of acetoacetic acid esters of formula (III, in turn obtained by reaction of diketene (IV) with an alcohol), wherein R1 is as defined above by reaction with sodium nitrite in the presence an acid to give the oxyiminated product (II), wherein R is hydrogen. The oxyiminated compound of formula (II), wherein R is hydrogen on alkylation with appropriate alkylating agents gives the substituted oxyiminated derivatives of formula (II), wherein R is a protective group. 
Method 2: Bromination of diketene of formula (IV) to give the dibromo derivative (V), which on reaction with an alcohol R1—OH gives the bromoester of formula (VI), which on further oxyimination with sodium nitrite in the presence of an acid gives the oxyiminated product of formula (II), wherein R is hydrogen. As mentioned hereinabove, the oxyiminated compounds of formula (II), wherein R is hydrogen on alkylation with appropriate alkylating agents give the substituted oxyiminated derivatives of formula (II), wherein R is a protective group.
The chemistry employed in the two general methods is summarised in Scheme-I.
Commercially, the compounds of formula (I) are manufactured by Method-1, since many of the acetoacetic acid ester derivatives of formula (III) are readily available. Method-2, on the other hand has limited application and is restricted to those manufacturers who in turn produce diketene. Moreover, the dibromo derivatives (V) being unstable cannot be stored and are therefore, not available commercially.
The prior art methods whereby compound of formula (I) is produced by Method-1 are summarised hereinbelow:
i) EP Patent No. 0 030 294 (Montavon et. al.) describes preparation of compound (I), wherein R is methyl from compound (II), wherein R has the same meaning as defined above and R1 is a tert-butyl group comprising first hydrolysis of the tert-butyl ester group with trifluoroacetic acid to give the corresponding free carboxylic acid derivative, which is brominated with about 0.72 moles of bromine per mole of the hydrolysed derivative in a mixture of dichloromethane and methanol to give the crude brominated compound (I), which is crystallised from carbon tetrachloride in an overall yield of 36%.
The shortcomings of the method are that it involves a) two step process of hydrolysis and halogenation, b) use of large excess (about 12 molar excess, thereby increasing the cost of manufacture) of the toxic and corrosive trifluoroacetic acid for hydrolysis the excess amount of which is removed by distillation thereby subjecting the unstable oxymino butyric acid to heat, c) formation of di- and polybromo derivatives and other impurities during bromination affecting the quality of the product and d) which necessiates purification taking recourse to crystallisation of the impure material from carbon tetrachloride, a highly toxic and suspected carcinogenic solvent.
A similar method is described in GB Patent No. 2 012 276 whereby compound of formula (I) is obtained first by hydrolysis of the group R1 (methyl or ethyl) in compound (II) using alkali, followed by halogenation of the free carboxylic acid derivative thus obtained.
ii) The alkaline hydrolysis, however, proceeds in low yields, implying formation of considerable amounts of impurities.
iii) The method described in EP Patent Nos. 0 324 418 and 0 325 183 (Naito et. al.) comprise hydrolysis of the group R1 (tert-butyl) of tert-butyl-2-methoxyimino-3-oxo butyrate by bubbling dry hydrogen chloride gas into a solution of the oxyimino ester in an anhydrous organic solvent selected from halogenated hydrocarbons, tetrahydrofuran and dioxane. The hydrolysed free carboxylic acid derivative thus obtained is brominated using bromine in presence of dichloromethane and a solution of hydrogen bromide in acetic acid. The brominated compound (I, R=methyl) after purification is obtained in an overall yield of only 11.60% from the starting ester compound.
In addition to involving a two-step process and proceeding in overall low yields the hydrolysis step is very slow and takes about 13-23 hours for completion. Moreover, the method utilises hazardous tetrahydrofuran and the industrially not accepted dioxane for hydrolysis.
iv) In the method disclosed in EP Patent No. 0 246 603 (Tani et. al.) a 2-oxyimino-3-oxo-butyric acid ester is reacted with a silylating agent to produce the corresponding 3-silyloxy derivative, which is halogenated at the 4-position. Hydrolysis of the ester protective group gives compounds of formula (I).
However, the shortcomings of the method are, a) an additional step of silylation, adding to the cost of manufacture, b) utilisation of very low temperature (Ca. −30° C.) for halogenation and c) purification of the halogenated derivative by chromatography, not practical on industrial scale.
v) Tani et. al. in EP Patent No. 0 416 857 claim a one-pot and one-step synthesis of compounds of formula (I) by subjecting the tert-butyl ester of compound (II) to bromination in an etherial solvent or a mixture of ether and inert solvent selected from carbon tetrachloride, toluene and benzene. Two molar equivalents of bromine per mole of the ester is employed. The final compound (I) is obtained in a yield of 42-46%.
The major disadvantage of the method is the use of ether solvents, which are prone to explosion and use of toxic and carcinogenic carbon tetrachloride and benzene.
To summarise, the methods described in the prior art for synthesis of 4-bromo-2-oxyimino butyric acid (I) from the ester derivative (II) suffer from one or more of the following shortcomings. These are, viz.                a) separate steps for hydrolysis of the ester group R1 and bromination at the 4-position,        b) use of toxic, corrosive and costly chemicals like trifluoroacetic acid for hydrolysis,        c) utilisation of tetrahydrofuran and etherial solvents, which are prone to explosion and utilisation of environmentally benign solvents such as benzene, carbon tetrachloride and dioxane for the hydrolysis, bromination and purification/crystallisation steps,        d) use of bromine in up to two molar equivalents of the starting ester, leading to formation of considerable amounts of di- and poly-brominated derivatives and other impurities,        e) necessity of removing the impurities by crystallisation from a solvent or mixture of solvents or through chromatography,        f) shortcomings a) to e) leading to overall low yield, increase in time and cost of manufacture and environmentally benign processes for manufacture of compounds of formula (I) and        g) finally, shortcoming f) in turn, leading to lower conversions and lower yields when compounds of formula (I) are utilised as intermediates for synthesis of commercially important cephalosporin antibiotics carrying a 2-(2-aminothiazol-4-yl)-2-oxyimino acetic acid group attached to the 7-amino position of the β-lactam nucleus.        